PL87801B1 - Amino pyrimidines[us3635978a] - Google Patents

Amino pyrimidines[us3635978a] Download PDF

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Publication number
PL87801B1
PL87801B1 PL1970166422A PL16642270A PL87801B1 PL 87801 B1 PL87801 B1 PL 87801B1 PL 1970166422 A PL1970166422 A PL 1970166422A PL 16642270 A PL16642270 A PL 16642270A PL 87801 B1 PL87801 B1 PL 87801B1
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Poland
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formula
acid
amino
hydroxy
group
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PL1970166422A
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Polish (pl)
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University Of Strathclyde Te Glasgow Grootbrittannie
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Publication of PL87801B1 publication Critical patent/PL87801B1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48Two nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D475/00Heterocyclic compounds containing pteridine ring systems
    • C07D475/02Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
  • Furan Compounds (AREA)

Abstract

1303171 Pteridine derivatives STRATHCLYDE UNIVERSITY OF 23 Jan 1970 [28 Jan 1969] 3301/70 Heading C2C The novel pteridine derivative tautomeric forms or salts thereof are prepared by a light stage synthesis, the steps being (1) condensation of phthalic anhydride with 2- aminoisobutyric acid, to form N-phthalyl-2- aminoisobutyric acid (II), (2) formation of the acid chloride, (3) reaction of the acid chloride with diazomethane to form 1 -diazo-3-methyl-3- plitholimido-buton -2 -oae (IV) (4) hydrolysis of the diazo group to primary hydroxyl group (V), (5) hydrolysis of the imide group to yield 3- amino - 1 - hydroxy - 3 - methylbutan - 2 - o4e VI as its hydsochloride, (6) formation of the semicarbazone VII, (7) condensation at the primary amine group with 2-amino-4-chloro-6- hydroxy - 5 - nitropyrimidine, (8) reductive cyclization to yield I above. Pharmaceutical compositions of compound I or, pharmaceutically acceptable salts thereof with the usual excipients show anti-microbial activity when administered parenterally or orally. [GB1303171A]

Description

Przedmiotem wynalazku jest sposób wytwarza¬ nia nowej 2-amiiino-4-i(l/,l'-dwumetylo-3,-hydroksy- -acetonylo)-aminjO-6-hydroksy-5^nitropirymidyny o wzorze 1. Zwiazek ten jest produktem wyjsciowym do wytwarzania 2-amino-4-hydroksy-6-hydroksy- 5 -metylo- 7,7-dwumetylo- 7,8 - dwuwodoropterydy- ny, bedacej cennym srodkiem bakteriostatycznym.Sposobem wedlug wynalazku 2-amino-4-(l',l'- -dwumetylo-3'-hydroksyacetony!lo)- amino-6-hydro- ksy-5-niitropirymidyne wytwarza sie dzialajac kwa- 10 sem na semikarbazon ketonu pirymidynyloamino- wego o wzorze 2. Stosuje sie w tym celu kwas 0 umiarkowanej mocy, zwlaszcza kwas organiczny, np. kwas trójfluorooctowy lub benzenosulfonowy, albo kwas mineralny, korzystnie rozcienczony, np. 15 rozcienczony kwas solny lub siarkowy.Reakcje prowadzi sie korzystnie w temperaturze wrzenia mieszaniny reakcyjnej w ciagu kilku do kilkunastu minut, po czym mieszanine chlodzi sie, przesacza i przesacz zobojetnia, korzystnie wodóro- 20 tlenkiem amonowym. Wytracony zwiazek o wzorze 1 odsacza sie i oczyszcza znanymi sposobami.Zwiazek o wzorze 2, bedacy produktem wyjscio¬ wym w procesie prowadzonym sposobem wedlug wynalazku, jest zwiazkiem nowym. Wytwarza sie 25 go latwo przez reakcje semikarbazonu 3-amino-l- -hydroksy-3-metylobutanonu-2 lub jego soli, ko¬ rzystnie chlorowodorku o wzorze 3, z 2-amino-4- -chlorowco-6-hydroksy-5-nitropirymidyna. Reakcje prowadzi sie w obecnosci srodka wiazacego kwas, 30 takiego jak np. weglan sodowy lub trzeciorzedowa amina, np. trójetyloamina.Zwiazek o wzorze 3 jest równiez zwiazkiem no¬ wym i wytwarza sie go przez dzialanie semikarba- zydem lub jego sola na 3-amino-l-hydroksy-3-rne- tylobutanon-2 lub jego sól, korzystnie chlorowodo¬ rek o wzorze 4.# Reakcje prowadzi sie korzystnie w obecnosci substancji buforowej, np. octanu lub weglanu sodowego.Zwiazek o wzorze 4 jest takze zwiazkiem nowym i otrzymuje sie go w ten sposób, ze.na 1-hydrok- sy-3-metylo-3-ftaloimidobutanon-2 o wzorze 5 dzia¬ la sie kwasem, korzystnie mocnym kwasem, ta¬ kim jak kwas solny, bromowodorowy lub siarko¬ wy.Zwiazek o wzorze 5 jest równiez zwiazkiem no¬ wym i wytwarza sie ,go dzialajac kwasem na 1- -dwuazO'-3-ftaloi:midobutainon-2 o wzorze 6. Jako kwas stosuje sie korzystnie rozcienczony kwas mi¬ neralny, zwlaszcza rozcienczony kwas siarkowy.Zwiazek o wzorze 6 jest takze zwiazkiem nowym i wytwarza sie go na przyklad przez reakcje dwu- azometanu z chlorkiem kwasu N-ftalilo-2-amino- izomaslowego, bedacego zwiazkiem znanym. Ko¬ rzystnie stosuje sie nadmiar dwuazometanu, np. ilosc dwukrotnie wieksza od wynikajacej z obli¬ czen stechiometrycznych, w celu zwiazania kwasu pozostajacego podczas reakcji.Przyklad. Mieszanine 6,0 g chlorowodorku semikarbazonu ketonu pirymidynyloaminowego o 87 80187 801 wzorze 2 i 100 ml 2n kwasu solnego utrzymuje sie w stanie wrzenia pod chlodnica zwrotna w ciagu minut, a nastepnie chlodzi sie i przesacza. Do przesaczu wkrapla sie mieszajac wodorotlenek amonowy o gestosci 0,880 az do uzyskania odczynu 5 obojetnego, po czym odsacza sie wydzielona 2-ami- no-4-(l'.l/-dwumetyilo-3'-hydroksyaeetonylo) -ami- no-6-hydroksy-5-nitropirymidyne i przemywa wo¬ da, etanolem i eterem. Otrzymuje sie produkt o barwie zóltawobialej, o temperaturze topnienia 10 218°C Stosowany w tym przykladzie jako produkt wyjsciowy zwiazek o wzorze 2 wytwarza sie w nastepujacy sposób* Roztwór dwuazometanu w ete¬ rze, nie zawierajacy alkoholu, otrzymany przez rozpuszczenie 136 g preparatu Diazald w 950 ml 15 eteru, wkrapla sie do mieszaniny zawierajacej roz¬ twór 40,9 g wodorotlenku potasowego w 70 ml wody, 240 ml glikolu dwuetyilenowego i 70 ml ete¬ ru, ogrzanej do temperatury 65—70°C na lazni wodnej. Powstajacy dwuazometan oddestylowuje 20 sie powoli traktuje roztworem 51,1 g chlorku kwa¬ su N-ftalilo-2-aminoizomaslowego w 700 ml eteru.Mieszanine wytrzasa sie i pozostawia na okres no¬ cy w temperaturze pokojowej, po czym odparo¬ wuje eter pod zmniejszonym cisnieniem, otrzy- 25 mujac l-dwuazo-3-metylo-3-ftalimidobutanon-2 ó wzorze 6 w postaci krysztalów o barwie jasnozól- tej. 50 g otrzymanego produktu miesza sie z 500 ml 0,5n kwasu siarkowego i ogrzewa do temperatury 30 80°C, zapoczatkowujac proces hydrolizy. Po ustaniu wydzielania sie gazu mieszanine wlewa sie do 1 litra lodowatej wody, odsacza otrzymany 1-hydrok- sy-3-metylo-3-ftalimidofoutanon-2 o wzorze 5 i przemywa 50 ml wody, a nastepnie przekrystali- 35 zowuje z wodnego roztworu etanolu, dodajac wegla aktywowanego. Otrzymuje sie czysty produkt kry¬ staliczny o barwie jasnozóltej, topniejacy w tem¬ peraturze 118CC. g otrzymanego produktu traktuje sie 400 ml 40 6n kwasu solnego i utrzymuje w stanie wrzenia pod chlodnica zwrotna w ciagu 2Va godziny, po czym chlodzi, odsacza wykrystalizowany kwas ftar Iowy (19 g) i przesacz odparowuje do sucha pod zmniejszonym cisnieniem. Pozostalosc rozpuszcza sie w 50 ml etanolu, dodaje 250 ml eteru i odsa¬ cza wytracony chlorowodorek 3-amino-l-hydroksy- -3-metylobutanonu-2 o wzorze 4. 1 mol chlorowodorku semikarbazydu rozpuszcza sie w mozliwie malej ilosci wody dodajac 1 mol wodoroweglanu sodowego i miesza az do ustania wydzielania sie gazu. Nastepnie dodaje sie porcja¬ mi 1 mol chlorowodorku aminoketonu o wzorze 4 i mieszajac ogrzewa na lazni parowej w ciagu 30 minut, po czym chlodzi i odsacza wykrystalizowa¬ ny chlorowodorek semikatfbazonu o wzorze 3, prze¬ mywa osad etanolem i eterem. Otrzymany piodukt ma temperature topnienia 208°C i stosuje sie go do dalszej fazy procesu bez oczyszczania. 6,8 g tego produktu miesza sie z 6,0 g z 2-amino- -4-chloro-6-hydroksy-5-nitropirymidyny, 10 ml trójetyloaminy i 450 ml etanolu i mieszanine u- trzymuje w stanie wrzenia pod chlodnica zwrotna w ciagu 18 godzin, po czyni ichlodzi i odparowuje do objetosci 200 ml. Po ochlodzeniu odsacza sie; wydzielony osad, otrzymujac 6,0 g semikarbazonu ketonu pirymidynyloaminowego o wzorze 2. Pro¬ dukt ma barwe bezowa i topnieje w temperaturze 206—210°C. PLThe subject of the invention is a process for the preparation of a novel 2-amino-4-i (1,1'-dimethyl-3, -hydroxy-acetonyl) -aminjO-6-hydroxy-5-nitropyrimidine of formula 1. This compound is a product of the starting material for the production of 2-amino-4-hydroxy-6-hydroxy-5-methyl-7,7-dimethyl-7,8-dihydropteridine, which is a valuable bacteriostatic agent. 2-amino-4- (1 ' , l'-dimethyl-3'-hydroxyacetones! l) -amino-6-hydroxy-5-niitropyrimidine is prepared by treating the pyrimidinylamino ketone semicarbazone of formula 2 with an acid. of moderate strength, especially an organic acid, e.g. trifluoroacetic acid or benzenesulfonic acid, or a mineral acid, preferably dilute, e.g. dilute hydrochloric or sulfuric acid. The reactions are preferably carried out at the boiling point of the reaction mixture for a few to several minutes, then the mixture is cooled down sieves, slides and slides neutralize, preferably ammonium hydroxide. The precipitated compound of formula I is filtered off and purified by conventional methods. The compound of formula II, which is a starting product of the process according to the invention, is a novel compound. It is readily prepared by reacting 3-amino-1-hydroxy-3-methylbutanone-2 semicarbazone or a salt thereof, preferably a hydrochloride of formula III, with 2-amino-4-halo-6-hydroxy-5-. nitropyrimidine. The reactions are carried out in the presence of an acid-binding agent, such as, for example, sodium carbonate or a tertiary amine, for example, triethylamine. The compound of formula III is also a novel compound and is prepared by treatment with semicarbazide or its salt on the 3-amino -1-hydroxy-3-n-2-butanone-2 or a salt thereof, preferably a hydrochloride of formula 4. The reaction is preferably carried out in the presence of a buffer substance, for example sodium acetate or carbonate. The compound of formula IV is also a novel compound and it is obtained by treating the 2-1-hydroxy-3-methyl-3-phthalimidobutanone of the formula 5 with an acid, preferably a strong acid, such as hydrochloric, hydrobromic or sulfuric acid. The compound of formula V is also a novel compound and is prepared by treating it with an acid on 1-diazotium-3-phthaloyl: midobutainone-2 of formula 6. The acid is preferably dilute mineral acid, in particular dilute acid. The compound of formula 6 is also a new compound and is produced, for example, by pr by reaction of diazomethane with N-phthalyl-2-aminoisobutyric acid chloride, which is a known compound. Preferably an excess of diazomethane, for example twice the amount resulting from the stoichiometric calculations, is used to bind the acid remaining in the reaction. A mixture of 6.0 g of pyrimidinyl amine ketone semicarbazone hydrochloride 87 80187 801 of formula 2 and 100 ml of 2N hydrochloric acid is refluxed for minutes, then cooled and filtered. Ammonium hydroxide with a density of 0.880 is added dropwise to the filtrate, while stirring, until it is neutral, and then the separated 2-amino-4- (1'1 / -dimethyl-3'-hydroxyeetonyl) -amino-6 is filtered off. -hydroxy-5-nitropyrimidine and washed with water, ethanol and ether. A yellowish-white product with a melting point of 10,218 ° C is obtained. The compound of formula II used in this example is prepared as follows: An alcohol-free ether diazomethane solution obtained by dissolving 136 g of Diazald in 950 ml of ether are added dropwise to a mixture containing a solution of 40.9 g of potassium hydroxide in 70 ml of water, 240 ml of diethylene glycol and 70 ml of ether, heated to 65-70 ° C in a water bath. The resulting diazomethane is distilled off slowly and the ether is slowly evaporated with a solution of 51.1 g of N-phthalyl-2-aminoisobutyric acid chloride in 700 ml of ether. The mixture is stirred and allowed to stand for a night at room temperature, then the ether is evaporated under reduced pressure. pressure to give 1-diazo-3-methyl-3-phthalimidobutanone-2, formula 6 as light yellow crystals. 50 g of the product obtained is mixed with 500 ml of 0.5N sulfuric acid and heated to 80 ° C, initiating the hydrolysis process. After gas evolution has ceased, the mixture is poured into 1 liter of ice-cold water, the obtained 1-hydroxy-3-methyl-3-phthalimidofoutanone-2 of formula 5 is filtered off and washed with 50 ml of water and then recrystallized from an aqueous ethanol solution by adding activated carbon. A pure crystalline product, light yellow in color, melting at 118 ° C is obtained. g of the product obtained are treated with 400 ml of 40 6 N hydrochloric acid and refluxed for 2 hours, then cooled, the crystallized phthalic acid (19 g) is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ethanol, 250 ml of ether are added and the precipitated 3-amino-1-hydroxy-3-methylbutanone-2-hydrochloride of the formula 4 is filtered off. 1 mole of semicarbazide hydrochloride is dissolved in as little water as possible by adding 1 mole sodium bicarbonate and stir until gas evolution ceases. Thereafter, 1 mole of aminocetone hydrochloride of formula IV is added and, while stirring, heated on a steam bath for 30 minutes, it is cooled and the crystallized semicatphbazone hydrochloride of formula III is filtered off, washing the precipitate with ethanol and ether. The obtained product has a melting point of 208 ° C and it is used for the next stage of the process without purification. 6.8 g of this product is mixed with 6.0 g of 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine, 10 ml of triethylamine and 450 ml of ethanol, and the mixture is refluxed under reflux. 18 hours, after it is allowed to cool and evaporate to 200 ml. After cooling, it drips off; a precipitate was isolated to give 6.0 g of pyrimidinylamine ketone semicarbazone of the formula 2. The product is beige in color and melts at 206-210 ° C. PL

Claims (4)

Zastrzezenia patentowe 1. Sposób wytwarzania nowej 2-amino-4-(l',l'- -dwumetylo-3'-hydroksyacetonylo) -amino-6-hy- droksy-5-nitrcpirymidyny o wzorze 1, znamienny tym, ze semikarbazon ketonu pirymidynyloamino¬ wego o wzorze 2 poddaje sie reakcji z kwasem.Claims 1. A method for the preparation of a novel 2-amino-4- (1 ', 1'-dimethyl-3'-hydroxyacetonyl) -amino-6-hydroxy-5-nitropyrimidine of formula 1, characterized in that the ketone semicarbazone the pyrimidinylamine of formula II is reacted with the acid. 2. Sposób wedlug zastrz. 1, znamienny tym, ze stosuje sie kwas trójfluorooctowy lub benzenosul- fonowy.2. The method according to claim The process of claim 1, wherein trifluoroacetic or benzenesulfonic acid is used. 3. Sposób wedlug zastrz. 1, znamienny tym, ze stosuje sie kwas mineralny.3. The method according to p. The process of claim 1, wherein the mineral acid is used. 4. Sposób wedlug zastrz. 3, znamienny tym, ze stosuje sie kwas solny lub siarkowy.87 801 CH. + I HsN-C-C0CH20H.CL CH, Wzór 4 s CO. ^s /N-C-C0-CH20H C0X I CH3 Wzór 5 N-C-CO-CHN COx I CH3 Wzór 6 12 H2N OH AA CH, N -NH-C-COCH-OH l CH3 Wzór i OH N^VN°2 CH, CH20H CHsN.NH.C0.NH, Wzór 2 CH, + CL H5N-C-C-CHZ0H * i u * CHjN.NH.CO.NH? Wzór 3 PL4. The method according to p. The process of claim 3, wherein hydrochloric acid or sulfuric acid is used. 87,801 CH. + I HsN-C-C0CH20H.CL CH, Formula 4 s CO. ^ s / NC-C0-CH20H C0X I CH3 Formula 5 NC-CO-CHN COx I CH3 Formula 6 12 H2N OH AA CH, N -NH-C-COCH-OH l CH3 Formula i OH N ^ VN ° 2 CH, CH2OH CH2N.NH.C0.NH, Formula 2 CH, + CL H5N-CC-CHZOH * iu * CH3N.NH.CO.NH Model 3 PL
PL1970166422A 1969-01-28 1970-01-26 Amino pyrimidines[us3635978a] PL87801B1 (en)

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PL1970138382A PL82983B1 (en) 1969-01-28 1970-01-26 Amino pyrimidines[us3635978a]
PL1970166422A PL87801B1 (en) 1969-01-28 1970-01-26 Amino pyrimidines[us3635978a]

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US (1) US3635978A (en)
JP (1) JPS4813555B1 (en)
AR (1) AR192568A1 (en)
BE (1) BE745104A (en)
BR (1) BR6915073D0 (en)
CA (1) CA959490A (en)
CH (1) CH535249A (en)
DE (2) DE2056569B2 (en)
DK (1) DK140697B (en)
ES (1) ES375933A1 (en)
FI (1) FI50979C (en)
FR (1) FR2034499B1 (en)
GB (5) GB1303173A (en)
HU (1) HU162913B (en)
IL (2) IL39672A (en)
NL (1) NL169880C (en)
PL (2) PL82983B1 (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3959278A (en) * 1970-07-27 1976-05-25 Burroughs Wellcome Co. Method of synthesis of pteridines
GB1363064A (en) * 1970-07-27 1974-08-14 Wellcome Found Pyrimidine derivatives as intermediates in the synthesis of pteridines
ZA725322B (en) * 1971-08-05 1974-03-27 Wellcome Found Potentiating formulations
US4156725A (en) * 1972-08-01 1979-05-29 Burroughs Wellcome Co. Bacteriostatic biologically active compositions
GB1453831A (en) * 1972-08-01 1976-10-27 Wellcome Found Biologically active compounds and compositions
GB1451043A (en) * 1972-08-01 1976-09-29 Wellcome Found Biologicylly acitve compounds and compositions
US4036961A (en) * 1972-08-01 1977-07-19 Burroughs Wellcome Co. Pharmaceutical compositions containing pteridines
GB1454165A (en) * 1972-08-01 1976-10-27 Wellcome Found Biologically active compounds and compositions
US4073786A (en) * 1973-07-30 1978-02-14 Burroughs Wellcome Co. 2-Amino-4-hydroxy-6-hydroxymethyl-7,7-diethyl-7,8-dihydropteridine and the 7-spirocyclohexyl analogue thereof
JP3181375B2 (en) * 1992-05-30 2001-07-03 株式会社豊夢 Bonding tool, method for bonding structural members using the same, and bonding structure between structural members
JP4780834B2 (en) 1998-10-22 2011-09-28 フィリップ・ビー・ビー・モヘノ Novel pterin antineoplastic drugs

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2547501A (en) * 1946-12-10 1951-04-03 American Cyanamid Co Method of preparing 2-amino-4-hydroxy-6-methylol pteridine

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GB1303173A (en) 1973-01-17
DE2056569A1 (en) 1971-08-12
AR192568A1 (en) 1973-02-28
FR2034499B1 (en) 1973-12-21
FR2034499A1 (en) 1970-12-11
BR6915073D0 (en) 1973-07-17
IL39672A (en) 1972-12-29
NL7001122A (en) 1970-07-30
HU162913B (en) 1973-04-28
FI50979C (en) 1976-09-10
DE2056569C3 (en) 1980-02-21
IL33783A0 (en) 1970-03-22
BE745104A (en) 1970-07-28
CA959490A (en) 1974-12-17
CH535249A (en) 1973-03-31
ES375933A1 (en) 1972-09-01
IL33783A (en) 1972-09-28
PL82983B1 (en) 1975-12-31
GB1303172A (en) 1973-01-17
FI50979B (en) 1976-05-31
GB1303174A (en) 1973-01-17
GB1303171A (en) 1973-01-17
DE2003859A1 (en) 1971-04-08
DK140697B (en) 1979-10-29
DE2056569B2 (en) 1979-06-13
JPS4813555B1 (en) 1973-04-27
NL169880C (en) 1982-09-01
GB1303175A (en) 1973-01-17
US3635978A (en) 1972-01-18

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